Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells

Steiner, Alexandre A.; Chakravarty, Sumana; Rudaya, Alla Y.; Herkenham, Miles; Romanovsky, Andrej A.

doi:10.1182/blood-2005-11-4743

Cited by 85 publications

(63 citation statements)

References 20 publications

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“…By binding to and activating TLR-4 located on the fenestrated capillaries of the circumventricular organ in the blood brain barrier, they lead to release of prostaglandin E2 (PGE2) from the arachidonic acid pathway in cytoplasmic membranes [22][23][24]. Prostaglandin E2 is small molecule that easily diffuses across the blood brain barrier, binds to specific PGE2 receptors (EP3 receptor) in the preoptic area and then activates thermal neurons in the anterior hypothalamus to a higher thermal balance point [2,[22][23][24]. It is unclear whether microbial products also lead to elevation of the thermal balance point by gaining direct access to the brain through disruption of the BBS.…”

Section: The Humoral Pathwaymentioning

confidence: 99%

Fever, fever patterns and diseases called ‘fever’ – A review

Ogoina

2011

Journal of Infection and Public Health

234

163

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Summary Fever is a prominent feature of disease since antiquity. The febrile response is orchestrated by the central nervous system through endocrine, neurological, immunological and behavioural mechanisms. Other than a regulated rise in body temperature, fever is often accompanied by various sickness behaviours, changes in metabolic and physiological characteristics of body systems and alterations in immune responses. Fever and the febrile response, therefore, remain significant contributors to the pathogenesis, clinical presentation and outcome of many illnesses and diseases.This review highlights the pathophysiology of the febrile response and describes the fever types and patterns, including their clinical significance. The various medical illnesses called ''fever'' are also listed and the origins of their appellations discussed.

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Section: The Humoral Pathwaymentioning

confidence: 99%

Fever, fever patterns and diseases called ‘fever’ – A review

Ogoina

2011

Journal of Infection and Public Health

234

163

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“…These findings suggest that hematopoietically derived IL-6 of peripheral origin may play a role in generating the second phase of LPS induced fever. Previous work has suggested that the LPS recognition molecule Toll like receptor 4 (TLR4) on immune cells plays a critical role at the onset of the initial phase of fever, and that the later phases of fever are dependent in a redundant way on TLR4 on both hematopoietic and non-hematopoietic cells (Steiner et al, 2006). While those finding seem to indicate that signaling molecules, such as cytokines, released from immune cells initiates fever, they are in disagreement with the finding that the initiation of the febrile response elicited by intravenously administrated LPS precedes the appearance of IL-6 and other cytokines in the blood stream (Cartmell et al, 2000;Givalois et al, 1994;Roth et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

Hamzic

Tang

Eskilsson

et al. 2013

Brain, Behavior, and Immunity

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KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.Hamzic et al., page 3

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“…The same strategy has been used by others to investigate the contribution to the sickness syndrome of hematopoietic vs. non-hematopoietic expression of TLR4 (Chakravarty and Herkenham, 2005;Steiner et al, 2006a), MyD88 (Gosselin and Rivest, 2008;Ruud et al, 2013b), and IL-1R1 (Matsuwaki et al, 2014).…”

Section: Mice Strainsmentioning

confidence: 99%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells

Abstract: Lipopolysaccharide (LPS),

Cited by 85 publications

References 20 publications

Fever, fever patterns and diseases called ‘fever’ – A review

Fever, fever patterns and diseases called ‘fever’ – A review

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

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